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Abstract #60118 Published in IGR 16-4
Functional Analysis of FOXE3 Mutations Causing Dominant and Recessive Ocular Anterior Segment Disease
Islam L; Kelberman D; Williamson L; Lewis N; Glindzicz MB; Nischal KK; Sowden JCHuman Mutation 2015; 36: 296-300
Mutations in FOXE3 are associated with both recessive and dominant inheritance of severe anterior ocular malformations and glaucoma. However, functional analyses of putative pathogenic mutations have not been performed. We tested the hypothesis that variations in FOXE3 activity underlie the different modes of inheritance and disease phenotype. In band shift assays, three recessive mutants showed loss-of-function, one retained DNA binding activity, whereas two dominant mutants showed altered activity. All six mutants showed reduced transactivation function compared with wild-type, and modeling the heterozygous state resulted in an intermediate level of activity providing no evidence for dominant negative action. Our in vitro data are consistent with loss-of-function below a dosage sensitive threshold as a mechanism of action for recessive mutations, but indicate an altered mutant protein function rather than a haploinsufficient mechanism for dominant mutations. This study provides the first functional evidence demonstrating that FOXE3 mutations identified in patients impair protein function with differential effects.
Developmental Biology and Cancer, Birth Defects Research Centre, UCL Institute of Child Health, London, UK.
Full articleClassification:
3.4.2 Gene studies (Part of: 3 Laboratory methods > 3.4 Molecular genetics)
9.1.3 Syndromes of Axenfeld, Rieger, Peters, aniridia (Part of: 9 Clinical forms of glaucomas > 9.1 Developmental glaucomas)
2.4 Anterior chamber angle (Part of: 2 Anatomical structures in glaucoma)